Hepatocellular carcinoma (HCC) is the fifth most common and the third most lethal cancer worldwide, with increasing incidence in developed countries including the United States. It is estimated that 15-50% of HCC patients develop HCC in the absence of eminent etiological factors such as hepatitis viral infection and alcohol abuse. Emerging evidence has indicated that metabolic disorders, such as nonalcoholic fatty liver disease (NAFLD) and type-2 diabetes (T2D), are linked to HCC development, which may account for the increasing incidence of HCC in developed countries. However, mechanisms underlying the connection between these disorders and HCC remain largely unknown. Our laboratory has recently demonstrated that reduced nuclear receptor coactivator-5 (Ncoa5) expression is associated with 40% of human HCC specimens, and that haploinsufficiency of NCOA5 in heterozygous knockout male mice results in glucose intolerance, NAFLD and subsequent HCC. These suggest that a NCOA5 deficiency-driven pathogenic pathway is commonly shared by NAFLD, T2D and HCC. Therefore, we hypothesize that NCOA5 acts as a haploinsufficient tumor suppressor by controlling temporal expression of genes encoding key proinflammatory cytokines and lipogenic enzymes in the liver. Thus, dysfunction of NCOA5 induces gene expression programs promoting hepatic inflammation and lipogenesis, leading to HCC development. Our objective is to provide evidence that NCOA5 is a key regulator controlling hepatic inflammation and lipid metabolism and impairment of its function results in HCC development. This hypothesis will be tested by three specific aims: 1). Illustrate the molecular links between hepatic inflammation and HCC using cell specific Ncoa5 knockout mice; 2) Determine the molecular connections between NCOA5 deficiency-driven NAFLD and HCC; and 3) Determine the role of aberrant NCOA5 expression in human HCCs and establish a molecular relationship between NCOA5 deficiency-driven mouse and human HCCs. The approach is innovative, because it combines the use of genetics to control metabolic phenotypes and system-level bioinformatic methods with novel mouse models of HCC to understand the underlying oncogenic pathway and hidden key factors in hepatocarcinogenesis. The proposed research is significant because these studies will not only provide unique insight into the reciprocal relationship between metabolic diseases and HCC, but also new targets for the development of preventive and therapeutic approaches against HCC.